CYP3A5 mediates basal and acquired therapy resistance in different subtypes of pancreatic ductal ade

Pancreatic ductal adenocarcinoma (PDAC) covers almost 85% of pancreatic cancers, although ductal tissue represents 10% of the overall pancreatic volume. Malignant tissue is highly heterogeneous and drug resistance to treatments often develops, leading to poor outcome. However underlying mechanisms of resistance are not completely clear yet.

In this paper a previously identified stratification in three tumor subtypes, i.e. exocrine-like, classical and quasi-mesenchymal, was confirmed and two new markers (HNF1A and KRT81) for reliable tissue stratification were defined in patient-derived xenografts. Overall survival analysis over a period of 120 months revealed higher survival for exocrine-like PDAC patients. Interestingly, cell lines derived from exocrine-like tumors showed resistance to Taxol (paclitaxel) or Tyrosine Kinase Inhibitors (TKIs).

Further tests on differences among the PDAC subtypes highlighted a basal over-expression of Cytochrome 450 3A5 (CYP3A5) solely in exocrine-like cells. Proteins of Cytochrome 450 family are known to be involved in xenobiotics metabolism and are usually highly expressed in liver cells. This high expression suggests that exocrine-like cells are able to degrade TKIs. Moreover, CYP3A5 over-expression occurs in Paclitaxel-resistant classical and quasi-mesenchymal lines, thus confirming Cytochrome p450 induction and acquired drug resistance in other PDAC subtypes.

Overall, these findings prove that CYP3A5 might be used as predictor for therapy outcome and detoxification mechanisms. CYP3A5 inhibition might sensitize PDAC tissue to established drugs and increase survival rates in clinical practice.

Original article: Noll EM et al (2016) CYP3A5 mediates basal and acquired therapy resistance in different subtypes of pancreatic ductal adenocarcinoma. Nat Med. 2016 Mar;22(3):278-87. doi: 10.1038/nm.4038.